4-Amino-2-hydroxytolune (AHT) is an aromatic amine ingredient in oxidative hair colouring products. As skin contact occurs during hair dyeing, characterisation of dermal metabolism is important for ...the safety assessment of this chemical class. We have compared the metabolism of AHT in the human keratinocyte cell line HaCaT with that observed
ex-vivo in human skin and
in vivo (topical application versus oral (p.o.) and intravenous (i.v.) route). Three major metabolites of AHT were excreted, i.e.
N-acetyl-AHT, AHT-sulfate and AHT-glucuronide. When 12.5 mg/kg AHT was applied topically, the relative amounts of each metabolite were altered such that
N-acetyl-AHT product was the major metabolite (66% of the dose in comparison with 37% and 32% of the same applied dose after i.v. and p.o. administration, respectively).
N-acetylated products were the only metabolites detected in HaCaT cells and
ex-vivo whole human skin discs for AHT and
p-aminophenol (PAP), an aromatic amine known to undergo
N-acetylation
in vivo. Since
N-acetyltransferase 1 (NAT1) is the responsible enzyme, kinetics of AHT was further compared to the standard NAT1 substrate
p-aminobenzoic acid (PABA) in the HaCaT model revealing similar values for
K
m and
V
max. In conclusion NAT1 dependent dermal
N-acetylation of AHT represents a ‘first-pass’ metabolism effect in the skin prior to entering the systemic circulation. Since the HaCaT cell model represents a suitable
in vitro assay for addressing the qualitative contribution of the skin to the metabolism of topically-applied aromatic amines it may contribute to a reduction in animal testing.
Zusammenfassung
Hintergrund
Der Artikel gibt eine Übersicht über die Diagnostik des Ovarialkarzinoms, eine seltene, aber häufig letale Erkrankung. Die jüngste Entwicklung auf dem Gebiet hat gezeigt, ...dass es sich beim Ovarialkarzinom tumorbiologisch nicht um eine Erkrankung, sondern vielmehr um verschiedene Subtypen mit jeweils spezifischer Pathogenese, Morphologie, Molekularpathologie und Prognose handelt.
Methode
Der Artikel basiert auf selektiver Literaturrecherche in PubMed und gängigen pathologischen Standardwerken sowie eigener Erfahrung in Diagnostik und konsiliarpathologischer Tätigkeit am Institut für Pathologie – Charité – Universitätsmedizin Berlin.
Ergebnisse
Der häufigste histologische Subtyp ist das seröse High-grade-Ovarialkarzinom; daneben gibt es die selteneren serösen Low-grade- sowie die endometrioiden, klarzelligen und muzinösen Ovarialkarzinome. Das seröse High-grade-Adenokarzinom entsteht nach aktueller Lehrmeinung auf dem Boden eines serösen tubaren intraepithelialen Karzinoms (STIC) und ist durch eine hohe Rate an p53-Mutationen und Defekte in der homologen Rekombination gekennzeichnet.
Das seröse Low-grade-Adenokarzinom entsteht hingegen über ein Borderline-Karzinom-Kontinuum und ist molekular durch pathologische Genmutationen von
KRAS
oder
BRAF
charakterisiert. Endometrioide und klarzellige Adenokarzinome entstehen am ehesten in Zusammenhang mit einer Endometriose und weisen daher entsprechende molekulare Aberrationen der Gene wie
PI3KCA, CTNNB1
und
ARID1A
auf. Weiterhin ist das endometrioide Adenokarzinom mit einer Mikrosatelliteninstabilität assoziiert. Der Ursprung muzinöser Ovarialtumoren ist weitestgehend unbekannt. Auch wenn ein Primarius im Gastrointestinaltrakt ausgeschlossen wird, ähneln sie morphologisch und molekular den kolorektalen Karzinomen.
Schlussfolgerung
Die molekularen Eigenheiten beeinflussen entscheidend die Prognose, den klinischen Verlauf, die Chemosensititvität und die Rezidivneigung. Translationale und klinische Studien dieses spannenden Gebiets sind notwendig, um tumorbiologische Besonderheiten herauszukristallisieren und multimodale innovative Therapiestrategien zu entwickeln.
We report the in situ formation of an ordered equilibrium decagonal Al-Pd-Mn quasicrystal overlayer on the fivefold symmetric surface of an icosahedral Al-Pd-Mn monograin. The decagonal structure of ...the epilayer is evidenced by x-ray photoelectron diffraction, low-energy electron diffraction, and electron backscatter diffraction. This overlayer is also characterized by a reduced density of states near the Fermi edge as expected for quasicrystals. This is the first time that a millimeter-size surface of the stable decagonal Al-Pd-Mn is obtained, studied, and compared to its icosahedral counterpart.
Scintillation cameras with options for detecting positron annihilation quanta in the coincidence acquisition mode may be the most innovative diagnostic devices introduced in nuclear medicine during ...the last few years. Besides conventional low-energy imaging in the collimated single-photon mode, these options offer a relatively inexpensive opportunity to perform uncollimated PET by switching into the coincidence acquisition mode. Instead of collimators, scatter frames (with 2 optional configurations: axial or open scatter frame) can be mounted to reduce the amount of quanta reaching the detectors from parts of the patient's body outside the field of view. This study investigates the coincidence imaging properties of the scintillation camera by measuring spatial resolution, scatter fraction, sensitivity, and count-rate response for 18F.
A needle in air and a plastic tube in water, each filled with 18F, were oriented axially and transversally to measure the transverse and axial spatial resolutions, respectively. Using either the axial or the open scatter frame, a standard cylinder filled homogeneously with activity was studied over several half-life periods to deduce the respective scatter and random fractions of the system by means of a sinogram technique. The activity of the cylinder was kept low to determine the sensitivity to coincidence events for both scatter frames.
Depending on the distance between the line source and the axis of rotation and on the choice of the axial acceptance angle used to reconstruct the coincidence events (single-slice rebinning algorithm), the axial resolution was found to be between 6 and 10 mm (full width at half maximum) with the axial scatter frame mounted. The transversal resolution was 6-6.5 mm on the axis of rotation, independent of the scatter frame used. The scatter fraction amounted to roughly 25% for the axial and 38% for the open scatter frames. The sensitivity when measuring true coincidence pairs ran to nearly 650 Hz/kBq/mL, when acquisition was performed with the axial scatter frame using a 30%-wide photopeak energy window. When acquiring with the open scatter frame, the sensitivity increased to nearly 3000 Hz/kBq/mL. Using the axial scatter frame, the homogeneously filled cylinder could be scanned with a maximum true coincidence rate of 2000 Hz for an activity of 55-60 MBq. Although this maximum true coincidence counting rate did not change significantly when the acquisition was performed with the open scatter frame, the respective activity in the standard cylinder was decreased to 10-15 MBq.
The spatial resolution of the scintillation camera is sufficient for high-resolution coincidence imaging. Compared with a dedicated PET scanner, the scatter fraction is relatively high and should therefore be corrected adequately. The relatively low sensitivity and the rather low maximum true coincidence counting rate are considerably inferior compared with a conventional PET scanner. However, these drawbacks can be partially compensated for, facilitating its clinical use.
Type 1 pili are the archetypal representative of a widespread class of adhesive multisubunit fibres in Gram-negative bacteria. During pilus assembly, subunits dock as chaperone-bound complexes to an ...usher, which catalyses their polymerization and mediates pilus translocation across the outer membrane. Here we report the crystal structure of the full-length FimD usher bound to the FimC-FimH chaperone-adhesin complex and that of the unbound form of the FimD translocation domain. The FimD-FimC-FimH structure shows FimH inserted inside the FimD 24-stranded β-barrel translocation channel. FimC-FimH is held in place through interactions with the two carboxy-terminal periplasmic domains of FimD, a binding mode confirmed in solution by electron paramagnetic resonance spectroscopy. To accommodate FimH, the usher plug domain is displaced from the barrel lumen to the periplasm, concomitant with a marked conformational change in the β-barrel. The amino-terminal domain of FimD is observed in an ideal position to catalyse incorporation of a newly recruited chaperone-subunit complex. The FimD-FimC-FimH structure provides unique insights into the pilus subunit incorporation cycle, and captures the first view of a protein transporter in the act of secreting its cognate substrate.
Using the ALADIN forward-spectrometer at SIS we have studied multi-fragment decays of
197Au projectiles after collisions with C, Al, Cu and Pb targets at a bombarding energy of
E
A
= 600
MeV
. The ...new data presented in this work comprise the measured cross sections of multifragment processes, the
N
Z
ratios of the produced fragments, and the differential distributions of fragment multiplicities and of observables built on the charge correlations within the event.
The
197Au+Cu data are analyzed with the statistical multifragmentation model. It is shown that all observables can be simultaneously reproduced on an absolute scale, apart from an overall normalization constant which relates the number of model events to the measured cross section. A continuous distribution of excited residual nuclei, used as input for the calculations, was derived from the criterion of a best fit to the data. It exhibits a correlation between decreasing mass number
A and increasing excitation energy
E
x
A
and a saturation of the excitation energy at
E
x
A
≈ 8
MeV
.
Zusammenfassung
Die meisten Flüsse der Erde sind durch interagierende soziale und natürliche Prozesse geformt und verändert worden. Als industrialisierte Flusslandschaften (Industrialized Riverine ...Landscapes – IRL) sind sie Teil unserer kritischen Infrastruktur geworden, entscheidend für den Nexus Wasser-Energie-Nahrung, aber auch geprägt durch Extremereignisse und anfällig für den Biodiversitätsverlust im Zuge des globalen Wandels. Diese Situation stellt das Management von Flusslandschaften vor große Herausforderungen und erfordert dringend einen interdisziplinären Ansatz, der Natur‑, Sozial- und Ingenieurwissenschaften integriert, um die Ursachen und den Verlauf des Wandels von Flusssystemen zu analysieren und zu Lösungsansätzen beizutragen. Das FWF-Doktoratsprogramm IRL baut auf der Doktoratsschule „HR21 – Human Rivers Systems in the 21st century“ (hr21.boku.ac.at) an der BOKU Wien auf und erforscht Flusslandschaften als gekoppelte sozio-ökohydrologische Systeme (SEHS). Im Rahmen von Promotionsprojekten werden die Ursachen des Wandels und der Wandel selbst analysiert und mögliche Zukunftsszenarien dargestellt. Die Erforschung von Flüssen als SEHS bringt neue Einsichten in die Koevolution von Natur und Gesellschaft als Wissensgrundlage in eine nachhaltigere Zukunft. Die Doktoratsschule ist in vier Forschungscluster gegliedert, die sich an wesentlichen Systemgrößen der aktuellen Fluss- und Nachhaltigkeitswissenschaft orientieren: (1) Konnektivität, (2) Governance und Planung, (3) Metabolismus und (4) Vulnerabilität. Die DoktorandInnen forschen gemeinsam mit Teams aus BOKU-WissenschaftlerInnen und internationalen KooperationspartnerInnen mit dem Ziel, ein umfassendes Verständnis der Kopplung von natürlichen mit sozialen Systemen zu erhalten. Drei Forschungsfelder, die gleichzeitig drängende Probleme in Flusslandschaften und für die Gesellschaft darstellen, bilden den thematischen Schwerpunkt der fünfzehn neuen Doktoratsprojekte: (1) Extremereignisse, (2) Infrastruktur und Urbanisierung und (3) der Nexus Wasser-Energie-Nahrung.
The transcriptional corepressor complex CoREST is one of seven histone deacetylase complexes that regulate the genome through controlling chromatin acetylation. The CoREST complex is unique in ...containing both histone demethylase and deacetylase enzymes, LSD1 and HDAC1, held together by the RCOR1 scaffold protein. To date, it has been assumed that the enzymes function independently within the complex. Now, we report the assembly of the ternary complex. Using both structural and functional studies, we show that the activity of the two enzymes is closely coupled and that the complex can exist in at least two distinct states with different kinetics. Electron microscopy of the complex reveals a bi-lobed structure with LSD1 and HDAC1 enzymes at opposite ends of the complex. The structure of CoREST in complex with a nucleosome reveals a mode of chromatin engagement that contrasts with previous models.
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•The activities of LSD1 and HDAC1 are closely coupled in the CoREST complex•Both LSD1 and HDAC1 exist in two different kinetic states•CoREST has a bi-lobed, flexible structure with the two enzymes located at opposite ends•CoREST interacts with methylated nucleosomes via LSD1, but not HDAC1 or RCOR1
Using a real-time NMR assay, Song et al. characterize crosstalk between LSD1 and HDAC1 in the CoREST complex. Activation or inhibition of one enzyme strongly affects activity of the other. Electron microscopy studies of the complex reveal a bi-lobed structure with implications for the mode of interaction with nucleosomes.
Background The probiotic Bifidobacterium longum NCC3001 normalizes anxiety‐like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis. Using a model of ...chemical colitis we test whether the anxiolytic effect of B. longum involves vagal integrity, and changes in neural cell function.
Methods Mice received dextran sodium sulfate (DSS, 3%) in drinking water during three 1‐week cycles. Bifidobacterium longum or placebo were gavaged daily during the last cycle. Some mice underwent subdiaphragmatic vagotomy. Behavior was assessed by step‐down test, inflammation by myeloperoxidase (MPO) activity and histology. BDNF mRNA was measured in neuroblastoma SH‐SY5Y cells after incubation with sera from B. longum‐ or placebo‐treated mice. The effect of B. longum on myenteric neuron excitability was measured using intracellular microelectrodes.
Key Results Chronic colitis was associated with anxiety‐like behavior, which was absent in previously vagotomized mice. B. longum normalized behavior but had no effect on MPO activity or histological scores. Its anxiolytic effect was absent in mice with established anxiety that were vagotomized before the third DSS cycle. B. longum metabolites did not affect BDNF mRNA expression in SH‐SY5Y cells but decreased excitability of enteric neurons.
Conclusions & Inferences In this colitis model, anxiety‐like behavior is vagally mediated. The anxiolytic effect of B. longum requires vagal integrity but does not involve gut immuno‐modulation or production of BDNF by neuronal cells. As B. longum decreases excitability of enteric neurons, it may signal to the central nervous system by activating vagal pathways at the level of the enteric nervous system.
Kinetic energies of light fragments ( A</=10) from the decay of target spectators in 197Au+197Au collisions at 1000 MeV per nucleon have been measured with high-resolution telescopes at backward ...angles. Except for protons and apart from the observed evaporation components, the kinetic-energy spectra exhibit slope temperatures of about 17 MeV, independent of the particle species, but not corresponding to the thermal or chemical degrees of freedom at breakup. It is suggested that these slope temperatures may reflect the intrinsic Fermi motion and thus the bulk density of the spectator system at the instant of becoming unstable.
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